Bierut and colleagues recently demonstrated that a polymorphism in the gene that encodes the alphas subunit, CHRNA5, is associated with nicotine dependence in human subjects. In addition, our group has shown that alphaS-containing nAChRs are involved in modulating nAChR function and also demonstrated that a polymorphism in the gene that encodes the mouse alphas subunit, ChrnaS, is associated with sensitivity to the high dose effects of nicotine. Nonetheless, the role of the nicotinic acetylcholine receptor (nAChR) alphas subunit in modulating the drug addiction process and brain function is poorly understood. In accordance with the overall goals of the COGEND Program Project, which are the identification of genes, environmental features, and biological mechanisms that predispose or protect individuals from the onset and persistence of nicotine dependence, we plan to conduct a series of experiments using three mouse genetic models of ChrnaS to address the basic mechanism(s) through which ChmaS/alphaS might contribute to nicotine addiction. The three mouse models we will utilize include!) Mice in which ChrnaS has been deleted (ChrnaS KO mice); 2) Mice in which naturally-occurring allelic variants of ChmaS have been exchanged between two inbred mouse strains (C3.D2Chma5 and D2.C3Chma5); and 3) Mice in which the human nonsynonymous SNP has been introduced (ChmaS D398N Kl). With these mouse models, we will 1) define the brain regions and neurotransmitter systems whose function is modulated by alphas containing nAChRs; and 2) determine the role of ChrnaS in regulating behaviors that can be modeled in mice that are thought to be components of the addiction process, including drug reinforcement, drug aversion, tolerance development and withdrawal. Because the influence of ChrnaS on drug abuse related phenotypes could occur in adolescence and/or adulthood, both age groups will be assessed for nAChR function and behavior. Relevance to public health: Genes are known to play a significant part in determining whether an individual will become a smoker. In this proposal, the influence of a genetic difference in a specific gene called ChrnaS will be studied in mice to determine how this gene might affect how an individual responds to the addictive substance in tobacco, nicotine. This study should provide information that will improve our understanding of how genes influence the use of nicotine-containing products.